Compositions and methods for prevention or reduction of carpa

Abstract

Provided herein are compositions and methods for preventing or reducing CARPA in a subject in need thereof. In one aspect, the composition comprises a therapeutic molecule, diagnostic molecule, molecular complex, or nanoparticle having a complement inhibitory protein attached thereto.

1 . A composition comprising:
 a) a therapeutic molecule, diagnostic molecule, molecular complex, or nanoparticle having a complement inhibitory protein attached thereto; or   b) a therapeutic molecule, diagnostic molecule, molecular complex, or nanoparticle having a peptide or aptamer that binds a complement inhibitory protein attached thereto.   
     
     
         2 . (canceled) 
     
     
         3 . The composition according to  claim 1 ,
 a) wherein the nanoparticle is a lipid nanoparticle or liposome;   b) wherein the nanoparticle is a protein-coated nanoparticle or polymeric nanoparticle;   c) further comprising a targeting moiety or moieties; and/or   d) wherein the complement inhibitory protein is selected from those in Table 1, or a functional variant or functional fragment thereof;   e) wherein the aptamer has a sequence of SEQ ID NO: 5, or a sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions as compared to SEQ ID NO: 5; and/or   f) wherein the therapeutic molecule, molecular complex, or nanoparticle is attached to the complement inhibitory protein by a flexible linker.   
     
     
         4 - 9 . (canceled) 
     
     
         10 . The composition according to claim  9 , wherein
 a) the linker comprises polyethylene glycol; and/or   b) the linker is from 500 to 2500 D.   
     
     
         11 . (canceled) 
     
     
         12 . The composition according to  claim 1 , wherein the complement inhibitory protein is a variant that includes unnatural amino acids and/or is truncated. 
     
     
         13 . (canceled) 
     
     
         14 . The composition according to  claim 1 , wherein the therapeutic molecule, molecular complex, or nanoparticle comprises a radionuclide. 
     
     
         15 . (canceled) 
     
     
         16 . The composition according to  claim 1 , comprising least or about 10 to about 30 complement inhibitory protein molecules per nanoparticle. 
     
     
         17 . The composition according to  claim 1 , comprising at least or about 10 to about 30 peptides or aptamers that bind a complement inhibitory protein per liposome or nanoparticle. 
     
     
         18 . The composition according to  claim 1 , wherein the liposome or nanoparticle comprises a therapeutic or diagnostic molecule or multimolecular complex encapsulated therein. 
     
     
         19 . (canceled) 
     
     
         20 . A medical device resistant to opsonization comprising:
 a) the medical device having a complement inhibitory protein attached thereto; or   b) the medical device having a peptide or aptamer that binds a complement inhibitory protein attached thereto.   
     
     
         21 . (canceled) 
     
     
         22 . The medical device according to  claim 20 , wherein
 a) the medical device comprises medical tubing, dialysis tubing, or a membrane;   b) the medical device comprises an implant, catheter, tubing for medical devices that contacts blood (e.g., cardiopulmonary bypass machines and hemodialysis/hemofiltration machines), functional components of medical devices that contact human blood (e.g., oxygenators used in extracorporeal membrane oxygenation; dialysis and ultrafiltration membranes used in renal replacement therapy);   c) the complement inhibitory protein is selected from those of Table 1   d) the aptamer has a sequence of SEQ ID NO: 5, or a sequence having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substitutions as compared to SEQ ID NO: 5; and/or   e) the medical device is attached to the complement inhibitory protein by a linker.   
     
     
         23 - 27 . (canceled) 
     
     
         28 . The medical device according to  claim 22 , wherein:
 a) the linker comprises polyethylene glycol; and/or   b) the linker is from 500 to 2500 Da.   
     
     
         29 . (canceled) 
     
     
         30 . The medical device according to  claim 20 , wherein the complement inhibitory protein is a variant that includes unnatural amino acids and/or is truncated. 
     
     
         31 - 32 . (canceled) 
     
     
         33 . The medical device according to  claim 20 , wherein the device encapsulates or releases a therapeutic or diagnostic molecule or multimolecular complex. 
     
     
         34 . The medical device according to  claim 33 , wherein the therapeutic or diagnostic molecule is rapamycin, paclitaxel, zotarolimus, or everolimus. 
     
     
         35 . A method comprising attaching a complement inhibitory protein, or an aptamer or peptide that binds a complement inhibitory protein, to a therapeutic molecule, molecular complex, liposome, or nanoparticle to generate a therapeutic composition capable of prolonged circulation time when administered to a subject. 
     
     
         36 . A method of preventing or reducing the severity of complement-activation-related pseudoallergy (CARPA) in a subject in need of therapeutic treatment, the method comprising administering to the subject a composition comprising a therapeutic molecule, molecular complex, liposome, or nanoparticle having a complement inhibitory protein or an aptamer or peptide that binds a complement inhibitory protein, attached thereto, wherein opsonization of the composition is prevented or reduced, thereby preventing or reducing the severity of CARPA in the subject. 
     
     
         37 . A method of treating in a subject in need of therapeutic treatment, the method comprising administering to the subject a composition comprising a therapeutic molecule, molecular complex, liposome, or nanoparticle having a complement inhibitory protein or an aptamer or peptide that binds a complement inhibitory protein, attached thereto, wherein the circulation time of the therapeutic molecule, molecular complex, liposome, or nanoparticle is increased as compared to the same therapeutic molecule, molecular complex, liposome, or nanoparticle without the complement inhibitory protein attached thereto. 
     
     
         38 . The method according to  claim 35 , wherein:
 a) the composition is the composition of  claim 1 ;   b) the therapeutic molecule, molecular complex, liposome, or nanoparticle comprises: mRNA, miRNA, siRNA, or DNA; protein therapeutics, including antibodies, enzymes, decoy receptors; peptides; small molecule drugs; with any of these drugs functioning as anti-hypertensives, vasopressors/inotropes, pro- or anti-coagulants, anti-inflammatories, antimicrobials, immunomodulators, nutrients, anti-cancer agents (chemotherapeutics), growth factors, or inhibitors of enzymes;   c) the nanoparticle is a lipid nanoparticle;   d) the nanoparticle is a protein-coated nanoparticle;   e) the complement inhibitory protein is selected from those of Table 1; and/or   f) the complement inhibitory protein is a variant that includes unnatural amino acids and/or is truncated; and/or   g) a targeting moiety is conjugated to the therapeutic composition.   
     
     
         39 - 46 . (canceled) 
     
     
         47 . The method according to  claim 38 , wherein;
 a) the linker comprises polyethylene glycol;   b) the linker is at least 500 Da; and/or   c) the linker is from 500 to 2500 Da.   
     
     
         48 - 51 . (canceled) 
     
     
         52 . The method according to  claim 35 ,
 a) wherein the therapeutic molecule, molecular complex, nanoparticle comprises a radionuclide;   b) comprising at least 10 complement inhibitory protein molecules per liposome or nanoparticle;   c) comprising at least 20 complement inhibitory protein molecules per liposome or nanoparticle; and/or   d) wherein the liposome or nanoparticle comprises a therapeutic or diagnostic molecule encapsulated therein.   
     
     
         53 - 60 . (canceled)